A selective GPR40 (FFAR1) agonist LY2881835 provides immediate and durable glucose control in rodent models of type 2 diabetes.

Abstract

LY2881835 is a selective, potent, and efficacious GPR40 agonist. The objective of the studies described here was to examine the pharmacological properties of LY2881835 in preclinical models of T2D. Significant increases in insulin secretion were detected when LY2881835 was tested in primary islets from WT mice but not in islets from GPR40 KO mice. Furthermore, LY2881835 potentiated glucose stimulated insulin secretion in normal lean mice. Acute administration of LY2881835 lowered glucose during OGTTs in WT mice but not in GPR40 KO mice. These findings demonstrate that LY2881835 induces GPR40‐mediated activity ex vivo and in vivo. LY2881835 was administered orally at 10 mg/kg to diet‐induced obese (DIO) mice (an early model of T2D due to insulin resistance) for 14 days. Statistically significant reductions in glucose were seen during OGTTs performed on days 1 and 15. When a study was done for 3 weeks in Zucker fa/fa rats, a rat model of insulin resistance, normalization of blood glucose levels equivalent to those seen in lean rats was observed. A similar study was performed in streptozotocin (STZ)‐treated DIO mice to explore glucose control in a late model of T2D. In this model, pancreatic insulin content was reduced ~80% due to STZ‐treatment plus the mice were insulin resistant due to their high fat diet. Glucose AUCs were significantly reduced during OGTTs done on days 1, 7, and 14 compared to control mice. In conclusion, these results demonstrate that LY2881835 functions as a GPR40‐specific insulin secretagogue mediating immediate and durable glucose control in rodent models of early‐ and late‐stage T2D.